Cellular and molecular alterations in GABAergic inhibitor circuits by mutations in MeCP2

Like autism, Rett syndrome arises in young children with a progressive loss of skills such as speech and control of movements, and is frequently accompanied by mental retardation and seizures. Mutations in the gene MECP2 are known to cause Rett syndrome. Josh Huang and his colleagues at Cold Spring Harbor Laboratory plan to study how the MECP2 gene regulates brain circuitry — information that may have implications for both Rett syndrome and autism.

Neurons in the brain transmit information by signaling from one cell to another in stereotypical circuits. Some of the neurons in these circuits excite their target neuron, whereas others inhibit the target cell’s activity. The balance of excitatory and inhibitory inputs is essential for the cells to detect signals and to prevent shorting out the circuit with over-activation, which can cause seizures.

Previous work has demonstrated that excitatory neurons require MECP2 for maturation; in the absence of the gene, excitatory neurons are smaller and have fewer signaling centers or synapses. The seizures associated with both Rett syndrome and autism, however, may indicate that the activity of excitatory neurons is not being ‘turned off’ by inhibitory neurons, tilting the balance of the neural circuits. Whether or not mutations in MECP2 would affect inhibitory neurons has not yet been determined, but Huang and colleagues plan to pursue this question.

The researchers intend to look for defects in synapse number and connectivity patterns in a mouse model of Rett syndrome by evaluating changes in the structure and function of inhibitory neurons. They plan to determine the properties of these cells using a short-lived green fluorescent protein that monitors the production of a key enzyme needed for the synthesis of GABA, the major inhibitory transmitter in the brain. They also plan to measure the electrical current in the inhibitory neurons and their targets to determine whether MECP2 is necessary for a cell’s normal activity and for the operation of neural circuits.

MECP2 encodes a protein that regulates gene expression, but few of its target genes are known. Huang and his team also plan to look for candidates by measuring gene expression levels in specific inhibitory neuron types, in normal and MECP2-deficient neurons with microarrays, using a technique that they pioneered. Based on these experiments, the researchers may find that mutations in MECP2 lead to weak or aberrant signaling between cells that disrupt the brain circuitry, potentially causing the behavioral, social and cognitive defects associated with Rett syndrome and autism.